11β-Hydroxysteroid dehydrogenase type 1 (11βHSD1) locally catalyzes the conversion of inactive glucocorticoids (cortisone in man) to active glucocorticoids (cortisol in man) in various tissues and organs, mainly the liver and the adipose tissue, but also in the muscles, bones, pancreas, endothelium, ocular tissue and in some parts of the central nervous system. 11βHSD1 acts as a regulator of the action of the glucocorticoids in the tissues and organs where it is expressed (Tomlinson et al., Endocrine Reviews, 25(5), 831-866 (2004), Davani et al., J. Biol. Chem., 275, 34841 (2000); Moisan et al., Endocrinology, 127, 1450 (1990)).
The most important pathologies in which glucocorticoids and inhibition of 11βHSD1 are involved are shown below.
A. Obesity, Type 2 Diabetes and Metabolic Syndrome
The role of 11βHSD1 in obesity, type 2 diabetes and metabolic syndrome (also known under the name of syndrome X or insulin resistance syndrome) where the symptoms include visceral obesity, glucose intolerance, insulin resistance, hypertension, type 2 diabetes and hyperlipidaemia (Reaven Ann. Rev. Med., 44, 121 (1993)) is described in numerous publications. In man, the treatment with carbenoxolone (a non-specific inhibitor of 11βHSD1) improves the insulin sensitivity in thin voluntary patients and in type 2 diabetics (Andrews et al., J. Clin. Endocrinol. Metab., 88, 285 (2003)). Furthermore, the mice whose 11βHSD1 gene has been switched off are resistant to the hyperglycemia induced by stress and obesity, show an attenuation of the induction of hepatic enzymes of gluconeogenesis (PEPCK and G6P) and exhibit an increase in insulin sensitivity in the adipose tissue (Kotelevstev et al., Proc. Nat. Acad. Sci., 94, 14924 (1997); Morton et al., J. Biol. Chem., 276, 41293 (2001)). Furthermore, transgenic mice where the 11βHSD1 gene has been overexpressed in the adipose tissues exhibit a phenotype similar to that of human metabolic syndrome (Masuzaki et al., Science, 294, 2166 (2001)). It should be noted that the phenotype observed exists without an increase in the total of the circulating glucocorticoids but is induced by the specific increase in active glucocorticoids in the adipose deposits.
Furthermore, novel categories of specific 11βHSD1 inhibitors have recently appeared:                arylsulfonamidothiazoles have shown that they improve insulin sensitivity and reduce the level of glucose in the blood of mice exhibiting hyperglycemia (Barf et al., J. Med. Chem., 45, 3813 (2002)). Furthermore, in a recent study, it has been shown that compounds of this type reduce food intake and the increase in weight by obese mice (Wang et al., Diabetologia, 49, 1333 (2006)).        triazoles have shown that they improve the metabolic syndrome and slow down the progression of atherosclerosis in mice (Hermanowski-Vosatka et al., J. Exp. Med., 202, 517 (2005)).        
B. Cognition and Dementia
Mild cognitive problems are common phenomena in elderly people and can result finally in progression to dementia. Both in the case of elderly animals and of elderly humans, the differences in individuals for the general cognitive functions have been related to the differences in long-term exposure to glucocorticoids (Lupien et al., Nat. Neurosci., 1, 69 (1998)). Furthermore, the deregulation of the HPA (hypothalamic-pituitary-adrenal) axis resulting in the chronic exposure to glucocorticoids of certain subregions of the brain has been proposed as contributing to the decline in the cognitive functions (McEwen et al., Curr. Opin. Neurobiol., 5, 205, 1995). 11βHSD1 is abundant in the brain and is expressed in numerous subregions, including the hypothalamus, the frontal cortex and the cerebellum (Sandeep et al., Proc. Natl. Acad. Sci., 101, 6734 (2004)). Mice deficient in 11βHSD1 are protected against the dysfunctionings of the hypothalamus associated with glucocorticoids which are related to old age (Yau et al., Proc. Nat. Acad. Sci., 98, 4716, (2001)). Furthermore, in studies in man, it has been shown that the administration of carbenoxolone improves verbal fluidity and verbal memory in elderly people (Yau et al., Proc. Natl. Acad. Sci., 98, 4716 (2001), Sandeep et al., Proc. Natl. Acad. Sci., 101, 6734 (2004)). Finally, the use of selective 11βHSD1 inhibitors of triazole type has shown that they extend the retention of memory in elderly mice (Rocha et al., Abstract 231 ACS Meeting, Atlanta, 26-30 Mar. 2006).
C. Intraocular Pressure
Glucocorticoids can be used by the topical route or systemic route for a great variety of pathologies of clinical opthalmology. A particular complication of these treatments is the glaucoma induced by the use of corticosteroids. This pathology is characterized by the increase in the intraocular pressure (IOP). In the most severe cases and for the untreated forms, the IOP can result in partial loss of field of vision and possibly in complete loss of vision. The IOP is the result of an imbalance between the production of aqueous humor and its drainage. The aqueous humor is produced in the nonpigmented epithelial cells and the drainage is carried out through these cells of the trabecular network. The 11βHSD1 is located in the nonpigmented epithelial calls and its function is clearly the amplification of the activity of the glucocorticoids in these cells (Stokes et al., Invest. Opthalmol. Vis. Sci., 41, 1629 (2000)). This notion is confirmed by the observation that the concentration of free cortisol is in high excess with respect to the cortisone in the aqueous humor (ratio 14/1). The functional activity of 11βHSD1 in the eyes was evaluated by studying the action of carbenoxolone in healthy volunteers. After treating with carbenoxolone for seven days, the IOP is reduced by 18% (Rauz et al., Invest. Ophtamol. Vis. Sci., 42, 2037 (2001)). The inhibition of 11βHSD1 in the eyes is thus predicted as reducing the local concentration of glucocorticoids and the IOP, producing a beneficial effect in the treatment of glaucoma and other disorders of vision.
D. Hypertension
The hypertensive substances resulting from the adipocytes, such as leptin and angiotensinogen, have been proposed as being key components in the hypertension pathologies related to obesity (Wajchenberg et al., Endocr. Rev., 21, 697 (2000)). Leptin, which is secreted in excess in transgenic aP2-11βHSD1 mice (Masuzaki et al., J. Clinical Invest., 112, 83 (2003)), can activate various networks of sympathetic neuronal systems, including those which regulate the arterial pressure (Matsuzawa et al., Acad. Sci., 892, 146 (1999)). Furthermore, the renin-angiotensin system (RAS) has been identified as being a determining route in the variation in arterial pressure. Angiotensinogen, which is produced in the liver and the adipose tissue, is a key substrate for renin and is the cause of the activation of the RAS. The plasma angiotensinogen level is significantly elevated in transgenic aP2-11βHSD1 mice, as are those of angiotensin II and of aldosterone (Masuzaki et al., J. Clinical Invest., 112, 83 (2003)); these components result in the elevation of the arterial pressure. The treatment of these mice with low doses of an angiotensin II receptor antagonist does away with this hypertension (Masuzaki et al., J. Clinical Invest., 112, 83 (2003)). These items of information illustrate the importance of the local activation of the glucocorticoids in the adipose tissue and the liver and suggest that this hypertension can be caused or exacerbated by the activity of 11βHSD1 in these tissues. The inhibition of 11βHSD1 and the reduction in the level of glucocorticoids in the adipose tissue and/or in the liver is thus predicted as having a beneficial role in the treatment of hypertension and the associated cardiovascular pathologies.
E. Osteoporosis
The development of the skeleton and the bone functions are also regulated by the action of the glucocorticoids. 11βHSD1 is present in the osteoclasts and osteoblasts. The treatment of healthy volunteers with carbenoxolone has shown a reduction in the bone resorption markers without change in the bone formation markers (Cooper et al., Bone, 27, 375 (2000)). The inhibition of 11βHSD1 and the reduction in the level of glucocorticoids in the bones might thus be used as a protective mechanism in the treatment of osteoporosis.
Piperidine or pyrrolidine urea derivatives which modulate the activity of 11βHSD1 have now been found.